Protein kinase D activation induces mitochondrial fragmentation and dysfunction in cardiomyocytes

作者：Bong Sook Jhun, Jin O‐Uchi, Stephanie M. Adaniya, Thomas Mancini, Jessica Cao, Michelle E. King, Amy K. Landi, Hanley Ma, Milla Shin, Donqin Yang, Xiaole Xu, Yisang Yoon, Gaurav Choudhary, Richard Clements, Ulrike Mende, Shey‐Shing Sheu · 发表于：The Journal of Physiology · 年份：2018 · DOI：10.1113/jp275418 · 被引用次数：57 · 研究领域：Mitochondrial Function and Pathology、ATP Synthase and ATPases Research、RNA and protein synthesis mechanisms

Key points Abnormal mitochondrial morphology and function in cardiomyocytes are frequently observed under persistent G q protein‐coupled receptor (G q PCR) stimulation. Cardiac signalling mechanisms for regulating mitochondrial morphology and function under pathophysiological conditions in the heart are still poorly understood. We demonstrate that a downstream kinase of G q PCR, protein kinase D (PKD) induces mitochondrial fragmentation via phosphorylation of dynamin‐like protein 1 (DLP1), a mitochondrial fission protein. The fragmented mitochondria enhance reactive oxygen species generation and permeability transition pore opening in mitochondria, which initiate apoptotic signalling activation. This study identifies a novel PKD‐specific substrate in cardiac mitochondria and uncovers the role of PKD on cardiac mitochondria, with special emphasis on the molecular mechanism(s) underlying mitochondrial injury with abnormal mitochondrial morphology under persistent G q PCR stimulation. These findings provide new insights into the molecular basis of cardiac mitochondrial physiology and pathophysiology, linking G q PCR signalling with the regulation of mitochondrial morphology and function. Abstract Regulation of mitochondrial morphology is crucial for the maintenance of physiological functions in many cell types including cardiomyocytes. Small and fragmented mitochondria are frequently observed in pathological conditions, but it is still unclear which cardiac signalling pathway is...